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E3 Ubiquitin Ligase TRIM21 Exacerbates Pathological Cardiac Hypertrophy Through ASK1 K63-Linked Polyubiquitination
Hongjie Shi1,2, Jing Xie1, Sha Hu2
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Summary
Tripartite Motif Containing 21 (TRIM21) drives pathological cardiac hypertrophy by activating the ASK1-JNK/p38 MAPK pathway. Inhibiting this TRIM21-ASK1 axis offers a potential therapeutic strategy for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Pathological cardiac hypertrophy is a significant risk factor for severe cardiovascular outcomes like heart failure.
- The intricate molecular mechanisms underlying cardiac hypertrophy are not fully elucidated.
- Identifying novel molecular players is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Tripartite Motif Containing 21 (TRIM21) in pathological cardiac hypertrophy.
- To elucidate the molecular mechanisms by which TRIM21 influences cardiac hypertrophy.
- To assess the therapeutic potential of targeting the TRIM21 pathway.
Main Methods:
- Utilized mouse models of cardiac hypertrophy (transverse aortic constriction) and in vitro cell culture systems (phenylephrine-stimulated cardiomyocytes).
- Performed TRIM21 knockdown and overexpression studies in vitro and in vivo.
- Investigated protein-protein interactions and post-translational modifications, including polyubiquitination of ASK1.
- Analyzed downstream signaling pathway activation (JNK/p38 MAPK) and employed pharmacological inhibition of ASK1.
Main Results:
- TRIM21 expression was significantly upregulated in hypertrophic cardiac models.
- TRIM21 knockdown attenuated cardiomyocyte hypertrophy, while overexpression exacerbated it.
- TRIM21 directly interacted with ASK1, promoting its K63-linked polyubiquitination and subsequent activation.
- Activation of JNK/p38 MAPK pathways was dependent on TRIM21 and ASK1.
- Pharmacological inhibition of ASK1 abrogated the pro-hypertrophic effects of TRIM21.
Conclusions:
- Identified a novel TRIM21-ASK1 signaling axis that drives pathological cardiac hypertrophy.
- TRIM21 promotes cardiac hypertrophy through ASK1-mediated activation of JNK/p38 MAPK pathways.
- TRIM21 represents a potential therapeutic target for treating hypertrophic heart disease and heart failure.
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